Introduction & objectives: Radical surgery is the mainstay of treatment for urothelial bladder cancer (UBC) and invasive upper tract urothelial cancer (UTUC) but, even when surgery is combined with cisplatin‐based (neo)adjuvant chemotherapy, recurrence rates are high. Many patients are ineligible for, do not respond to cisplatin-based chemotherapy, or refuse this treatment because of toxicity concerns. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in 60% of UTUC and 21–38% of muscle-invasive UBC and are candidates for targeted therapy. Infigratinib (BGJ398) is an ATP-competitive FGFR1–3 selective oral tyrosine kinase inhibitor that has shown clinical activity and tolerability in patients with advanced urothelial carcinoma (UC) harboring susceptible FGFR3 alterations. PROOF 302 was designed to investigate the efficacy and safety of adjuvant infigratinib versus placebo in patients with high-risk, muscle-invasive UC and susceptible FGFR3 alterations.
Materials & methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase 3 trial (NCT04197986). Eligible patients have high-risk, muscle-invasive UTUC or UBC (85% and 15%, respectively) with susceptible FGFR3 alterations (activating mutations, gene fusions, or rearrangements by FoundationOne® CDx test), and are ≤120 days following nephroureterectomy, distal ureterectomy, or cystectomy. The protocol was amended to include patients with carcinoma in situ, and those ineligible for or refusing cisplatin-based chemotherapy. Pathologic disease stage is ≥ypT2 and/or yN+ M0 after cisplatin-based neoadjuvant chemotherapy. For patients who are ineligible for, or have refused, cisplatin-based therapy, pathologic disease stage is: UTUC (≥pT2 pN0–2 M0 [post-lymphadenectomy or no lymphadenectomy]); UBC (≥pT3 or pN+). Patients are randomized 1:1 to receive oral infigratinib 125 mg or placebo, QD on days 1–21 every 28 days for up to 52 weeks (13 cycles) or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS), analyzed via stratified log-rank test, and Cox model (hazard ratio [HR]). Secondary endpoints: investigator-reviewed DFS; metastasis-free survival; overall survival; safety/tolerability. Exploratory endpoints: quality of life; pharmacokinetics, determination of the prevalence of genomic alterations and correlation with features of UC; genomic and proteomic assessment of tumor tissue and cell-free DNA samples from baseline and at recurrence to identify the predictive/prognostic value of biomarkers. Based on the HR of 0.5 for infigratinib vs. placebo, an interim analysis for adaptation and futility will be conducted after ~35 centrally confirmed DFS events. The initial sample size of 218 patients may be increased up to 328 patients based on an adaptive design. The power to detect a difference in DFS is 80%. PROOF 302 was initiated in March 2020 and is open internationally and expected to end in 2024.

A randomized, double-blind, placebo-controlled, phase 3 trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 genetic alterations: PROOF 302

For 2021, our focus remains: turning new data into your daily practice. The programme will consist of state-of-the-art lectures, case discussions and panel debates. Our faculty is a group of international & multidisciplinary experts.

We will take you on our journey to Ghent and beyond. Prior the congress, we send out case challenges, where you can compare your opinion with peers & experts. These cases will be part of the Global Congresses on Prostate & Bladder Cancer programme during the congress days (12 & 13 October for PROSCA and 14 & 15 October for BLADDR). After these days, you will be updated on prostate & bladder cancer management.